The Washington University SPORE in Leukemia is a highly dynamic translational cancer research program that focuses specifically on leukemias and myelodysplastic syndromes (MDS). We have assembled an outstanding group of investigators with complementary expertise in basic and clinical leukemia research. In this SPORE, we leverage expertise in cancer genomics, immunology, and hematopoiesis to develop innovative translational research in leukemia. Our long term goal is to develop novel biomarkers and treatments for leukemias and MDS and to recruit and promote innovative translational leukemia research. To achieve these goals, the following specific aims are proposed. Aim 1. To exploit recent advances in cancer genomics to develop novel biomarkers and treatments for leukemias and MDS. Washington University has been at the forefront of genomic studies in AML and MDS. Through sequencing of primary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) genomes, we identified several novel recurring mutations of genes involved in DNA methylation (DNMT3A and IDH1) and RNA splicing (U2AF1). This basic research has led to the development of the following two translational SPORE projects. Project 1. Molecular determinants of decitabine responsiveness Project 3. Development of RNA splicing modulators for myelodysplastic syndromes and AML. Aim 2. To leverage local expertise in immunology and hematopoiesis to develop novel treatments for leukemias and myelodvsplastic syndromes. Institutional expertise in basic immunology and hematopoiesis research has led to the development of two innovative translational projects in leukemia. Project 2. Targeting the bone marrow microenvironment in acute lymphocytic leukemia. Project 4. Epigenetic modulation of graft versus host disease and graft versus leukemia. Aim 3. To enhance the infrastructure that supports translational leukemia research. This SPORE will support the following Shared Research Resources: 1) Core A. Biospecimen Processing; 2) Core B. Biostatistics; and 3) Core C. Administration. Aim 4. To recruit and train new investigators in translational research. Aim 5. To facilitate inter-SPORE collaboration.